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The Elusive Multiple Self-Healing Squamous Epithelioma (MSSE) Gene: Further Mapping, Analysis of Candidates, and Loss of Heterozygosity

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The Elusive Multiple Self-Healing Squamous Epithelioma (MSSE) Gene: Further Mapping, Analysis of Candidates, and Loss of Heterozygosity Oncogene (2006) 25, 806–812 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc ONCOGENOMICS The elusive multiple self-healing squamous epithelioma (MSSE) gene: further mapping, analysis of candidates, and loss of heterozygosity S Bose1,5, LJ Morgan1, DR Booth2, DR Goudie3, MA Ferguson-Smith4 and FM Richards1 1Section of Medical and Molecular Genetics, Division of Reproductive and Child Health, University of Birmingham, Edgbaston, Birmingham, UK; 2Department of Pathology, University of Cambridge, Cambridge, UK; 3Department of Pathology, Ninewells Hospital and Medical School, Dundee, UK and 4Department of Clinical Veterinary Medicine, University of Cambridge, Cambridge, UK The MSSE gene predisposes to multiple invasive but self- 9q and a shared haplotype was revealed, suggesting a healing skin tumours (multiple self-healing epitheliomata). founder mutation (Goudie et al., 1993). Subsequently, we MSSE was previouslymapped to chromosome 9q22–q31 localized the MSSE region to 9q22.3, between D9S197 and a shared haplotype in affected families suggested a and D9S287/D9S1809 (Richards et al., 1997). Our founder mutation. We have refined the MSSE critical continued efforts to refine the MSSE critical region using region (o1 cM, o1 Mb) between the zinc-finger gene new polymorphic markers have been hampered by ZNF169 and the Fanconi anaemia gene FANCC.By ambiguitiesinthemapinthisregion,estimatedtobe genetic mapping we have excluded ZNF169 and FANCC 2.06 cM or 2.2 Mb, 93.34–95.54 Mb from NCBI Build as well as PTCH (PATCHED) and TGFBR1 (transform- 35.1, http://www.ncbi.nlm.nih.gov and Rutgers combined ing growth factor beta receptor type-1) genes. The linkage-physical map, build 35 (Kong et al., 2004). CDC14B cell cycle phosphatase gene also lies in the Chromosome 9q22.3 is relatively gene-rich and region but screening of the complete coding region harbours several possible candidate genes, including revealed no mutation in MSSE patients. Somatic cell PATCHED (PTCH), ZNF169 (encoding Kruppel–like hybrids created by haploid conversion of an MSSE zinc-finger protein), Fanconi Anaemia Complementa- patient’s cells enabled screening of the MSSE chromo- tion group-C (FANCC) and CDC14B. The Gorlin some 9 and showed no CDC14B deletion or mutation that Syndrome gene, PTCH, is a tumour suppressor gene abrogates CDC14B mRNA expression. Thus, CDC14B is (TSG) that is mutated or deleted in the majority of basal unlikelyto be the MSSE gene. We also report the first cell carcinomas of the skin (Gailani et al., 1996; molecular analysis of MSSE tumours showing loss of Holmberg et al., 1996). The ZNF169 gene was mapped heterozygosity of the MSSE region, with loss of the to the interval D9S196–D9S280 (Levanat et al., 1997) normal allele, providing the first evidence that MSSE is a and was therefore considered a candidate. Previously we tumour suppressor gene. have shown that MSSE families share an allele at an Oncogene (2006) 25, 806–812. doi:10.1038/sj.onc.1209092; EcoR1 RFLP in FANCC (Richards et al., 1997) thereby published online 19 September 2005 leaving it a possible candidate. The cell cycle regulatory phosphatase CDC14B regulates p53 (Li et al., 1997, Keywords: skin cancer; tumour suppressor gene; chro- 2000). The map position of CDC14B is ambiguous: mosome 9q22.3; CDC14B; MSSE according to radiation hybrid mapping it lies between D9S196 and D9S287 (GeneMap’99) within the MSSE critical region, but according to the genome sequence (NCBI Build 35.1) it is approximately 0.75 Mb distal to Introduction D9S287, outside the MSSE region. This discrepancy will be discussed later. Individuals with multiple self-healing squamous epithe- Here, we first narrowed down the MSSE interval by ONCOGENOMICS lioma (MSSE) develop multiple invasive skin tumours typing additional markers in MSSE families. Secondly, that undergo spontaneous regression leaving pitted scars, we have analysed possible candidates mapped within or with an age of onset between 8 and 62 years. MSSE shows close to the MSSE critical region, successfully excluding autosomal dominant inheritance, with most affected some of them. Thirdly, we have performed the first families originating in western Scotland. By linkage molecular analysis of MSSE tumours and have detected analysis, the MSSE gene was mapped to chromosome loss of heterozygosity (LOH), providing first evidence that MSSE is likely to be a TSG. Correspondence: Dr FM Richards; Current address: DanioLabs Ltd., 7330, Cambridge Research Park, Waterbeach, Cambs CB5 9TN, UK. Results E-mail: [email protected] 5Current address: Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Refining the genetic map of the MSSE interval Received 11 November 2004; revised 19 July 2005; accepted 25 July 2005; To reduce the MSSE interval, we performed haplotype published online 19 September 2005 analysis with nine new markers. However, due to gaps The MSSE skin tumour suppressor gene S Bose et al 807 and ambiguities in the physical map of this region, we first had to genetically map these markers (D9S119, FBP1, AFM070xb11, AFMa086yf1, AFM203wh8, AFMa350xg1, AFM023xh8, D9S1851, TGFBR1)by typing them in 15 CEPH and three Gorlin Syndrome families with known 9q22 recombinations, along with seven previously mapped markers (ZNF169, D9S280, D9S1816, D9S196, D9S197, D9S287, D9S1809). Posi- tional information from three Gorlin families and six CEPH recombinants (in families 1420, 1421, 13291 and 13292) allowed us to assemble an unambiguous genetic map of the region between D9S196 and D9S180 in relation to the background genetic map based on Genethon, Marshfield and deCODE genetic maps (Figure 1). This mapping enabled us to place TGFBR1 distal to D9S1809, outside the MSSE critical region. Similarly, a key recombinant demonstrated that AF- Ma086yf1 is proximal to FANCC. CDC14B was not mapped genetically because no polymorphisms were known. Our genetic map of these markers is in agreement with the latest assembled human genome sequence (NCBI Build 35.1), with the exception of AFMa086yf1. Our recombination data clearly places AFMa086yf1 prox- imal to FANCC, whereas the assembled genome sequence shows AFMa086yf1 distal to FANCC.We have not been able to find any other reports of genetic mapping of AFMa086yf1. It is important to note that D9S280 and D9S1851 were not given a physical location in the deCODE genetic map (Kong et al., 2002) because the authors were unable to resolve discrepancies between their genetic mapping and the physical draft sequence in this region. The more recent Rutgers combined linkage- Figure 1 Genetic map of 9q22–q31. Marker positions determined physical map (Kong et al., 2004) also does not include from genetic mapping data only (not physical data). The backbone D9S280, suggesting that genetic and physical maps on the left shows the combined data on markers from the Genethon and Marshfield sex-averaged linkage maps and deCODE could not be reconciled. We wonder if there is a genetic map, including chromosomal orientation and the approx- duplication in this region that has resulted in these imate genetic distance of 2 cM. To the right of the backbone is the discrepancies. This draws support from evidence of a genetic mapping data from the present study obtained from key duplicated D9S280 locus >2 Mb distal to the first recombinants in CEPH and Gorlin syndrome families. Vertical lines next to a marker name indicate the position of the marker D9S280, also distal to D9S287 in the annotated genome (e.g. AFM070xb11 is between D9S196 and FANCC). Arrows indi- sequence. cate that the possible position extends beyond limits of the map shown (e.g. D9S119 is proximal to D9S197). Sloping lines indicate the position of markers with respect to each other (e.g. AFM203wh8 Genotyping of intragenic polymorphisms excludes three is distal to AFMa086yf1 and proximal to AFMa350xg1 and AFM023xh8). CDC14B is not included because it has not been genes mapped genetically. The FANCC, ZNF169 and PTCH genes lie within the MSSE interval (D9S196–D9S287) and were thus con- polymorphism (C/G at nucleotide1504–51) showed that sidered as candidates. We have now typed intragenic the C allele segregates with the disease in affected LE polymorphisms in 11 MSSE families known to share a family members, in contrast to a G allele in other haplotype on chromosome 9q. families, thereby excluding PTCH as a candidate. Affected members of LE and BL families do not share the common allele at FANCC intron 2 (CAintr2) and the LE family also does not share the common allele at Haplotype analysis refines the MSSE interval FANCC intron 1 (CAintr1a) (Table 1). Also, affected To narrow down the MSSE critical region, we ana- members of families BL and LE did not share an allele lysed eight additional markers (D9S119, FBP1, with the rest of the families at a ZNF169 intronic AFM070xb11, AFMa086yf1, AFM203wh8, AF- microsatellite (Table 1). Thus, FANCC and ZNF169 Ma350xg1, AFM023xh8, and D9S1851) in the MSSE were both excluded as MSSE candidates. families (Table 1). Affected individuals from all of the 11 Earlier we had failed to exclude PTCH (Richards families previously known to share the 9q haplotype et al., 1997); however, typing of an additional PTCH were found to have at least one allele in common at each Oncogene The MSSE skin tumour suppressor gene S Bose et al 808 Table 1 Chromosome 9q haplotypes in MSSE families Polymorphic alleles on 9q13–9q31 segregating with the MSSE phenotype in 11 affected families. Shaded region indicates shared haplotypes. When two possible alleles are shown for an individual, it either indicates heterozygous state or that the phase could not be determined. When more than two alleles have been shown (e.g. in BL and LE), it indicates that all affected individuals within the family did not share a common allele. The relative positions of markers shown in bold have been confirmed by genetic linkage mapping. of these marker loci, with the exception of the most CDC14B is not mutated in MSSE patients distant families, BL and LE.
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